天然产物低毒性化合物对突变型 KRAS 肿瘤球体的生长抑制作用。

Growth Suppression of Cancer Spheroids With Mutated KRAS by Low-toxicity Compounds from Natural Products.

机构信息

Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.

Section of Otolaryngology, Department of Medicine, Fukuoka Dental College, Fukuoka, Japan.

出版信息

Anticancer Res. 2021 Aug;41(8):4061-4070. doi: 10.21873/anticanres.15207.

DOI:10.21873/anticanres.15207

PMID:34281875

Abstract

BACKGROUND/AIM: Among compounds from natural products selectively suppressing the growth of cancer spheroids, which have mutant (mt) KRAS, NP910 was selected and its derivatives explored.

MATERIALS AND METHODS

The area of HKe3 spheroids expressing wild type (wt) KRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS) were measured in three-dimensional floating (3DF) cultures treated with 18 NP910 derivatives. The 50% cell growth inhibition (GI50) was determined by long-term 3DF (LT3DF) culture and nude mice assay.

RESULTS

We selected NP882 (named STAR3) as the most effective inhibitor of growth of HKe3-mtKRAS spheroids with the least toxicity among NP910 derivatives. GI50s of STAR3 in LT3DF and nude mice assay were 6 μM and 30.75 mg/kg, respectively. However, growth suppression by STAR3 was observed in 50% of cell lines independent of KRAS mutation, suggesting that the target of STAR3 was not directly associated with KRAS mutation and KRAS-related signals.

CONCLUSION

STAR3 is a low-toxicity compound that inhibits growth of certain tumour cells.

摘要

背景/目的：在从天然产物中筛选出的选择性抑制具有突变型（mt）KRAS 的肿瘤球体生长的化合物中，选择了 NP910 并对其衍生物进行了探索。

材料和方法

在三维浮式（3DF）培养物中，用 18 种 NP910 衍生物处理表达野生型（wt）KRAS（HKe3-wtKRAS）和突变型 KRAS（HKe3-mtKRAS）的 HKe3 球体，测量其球体面积。通过长期 3DF（LT3DF）培养和裸鼠实验测定 50%细胞生长抑制（GI50）。

结果

我们选择了 NP882（命名为 STAR3）作为 NP910 衍生物中对 HKe3-mtKRAS 球体生长抑制作用最强且毒性最小的抑制剂。STAR3 在 LT3DF 和裸鼠实验中的 GI50 分别为 6 μM 和 30.75 mg/kg。然而，STAR3 对 50%的细胞系的生长抑制作用与 KRAS 突变无关，表明 STAR3 的作用靶点与 KRAS 突变和 KRAS 相关信号无关。